Our goal is to develop new treatments that will result in reduced morbidity and mortality from cancer. Preclinical data support the clinical development of the four treatment programs outlined in this application: 1. IUdR as a clinical radiation and chemotherapy sensitizer 2. Whole Body Hyperthermia as an enhancer of systemic anti-cancer treatment 3. Monoterpenes as anti-cancer drugs 4. Polyamine analogs as anti-cancer drugs We propose four years of integrated clinical and laboratory research focused within the conduct of Phase I clinical pharmacologic trials in each of these areas. Appropriate pharmacokinetic analyses and other biomarker assays will be done in all studies. Specifically, we will: a. Perform three to four Phase I trials testing IUdR as a radiosensitizer and/or chemosensitizer in rapidly proliferating, poorly responsive human tumors. The initial trial will study continuous IV infusion of IUdR and accelerated hyperfractionated radiotherapy in patients with high grade gliomas. Subsequent trials will evaluate: IUdR in combination with bleomycin/radiation in head and neck and esophageal cancers, IUdR in combination with cisplatin, and IPdR as an oral prodrug for IUdR. The latter will require establishment of an IND for IPdR through cooperation with CTEP. b. Conduct a phase I trial with dose escalation of L-PAM in patients receiving whole body hyperthermia. Changes in cytokines and nucleoside pools will be quantitated. The subsequent study will be whole body hyperthermia and L-PAM, in combination with Tumor Necrosis Factor and gamma-Interferon. c. Perform a Phase I trial of limonene to evaluate toxicity, metabolism and pharmacokinetics. Protein isoprenylation in lymphocytes and tumor tissue will be measured. Continued preclinical evaluation of more potent monoterpenes such as limonene perillyl alcohol will lead to subsequent phase I trials of these analogs. We will work with the NCI to establish INDs for these agents. d. Conduct Phase I clinical trials with two promising polyamine analogs, BE-4-4-4-4 and BE-3-7-3. The biologic endpoints of polyamine depletion and metabolite excretion as well as ornithine decarboxylase inhibition will be measured. Again IND application will be coordinated through the NCI and industry sponsors.